Unleashing ß-catenin with a new anti-Alzheimer drug for bone tissue regeneration.

ABSTRACT

The Wnt/ß-catenin signaling pathway is critical for bone differentiation and regeneration. Tideglusib, a selective FDA approved glycogen synthase kinase-3ß (GSK-3ß) inhibitor, has been shown to promote dentine formation, but its effect on bone has not been examined. Our objective was to study the effect of localized Tideglusib administration on bone repair. Bone healing between Tideglusib treated and control mice was analysed at 7, 14 and 28 days postoperative (PO) with microCT, dynamic histomorphometry and immunohistology. There was a local downregulation of GSK-3ß in Tideglusib animals, resulting in a significant increase in the amount of new bone formation with both enhanced cortical bone bridging and medullary bone deposition. The bone formation in the Tideglusib group was characterized by early osteoblast differentiation with down-regulation of GSK-3ß at day 7 and 14, and higher accumulation of active ß-catenin at day 14. Here, for the first time, we show a positive effect of Tideglusib on bone formation through the inactivation of GSK-3ß. Furthermore, the findings suggest that Tideglusib does not interfere with precursor cell recruitment and commitment, contrary to other GSK-3ß antagonists such as lithium chloride. Taken together, the results indicate that Tideglusib could be used directly at a fracture site during the initial intraoperative internal fixation without the need for further surgery, injection or drug delivery system. This FDA-approved drug may be useful in the future for the prevention of non-union in patients presenting with a high risk for fracture-healing.